"Emesis" and "emetic" refer to the process commonly known as vomiting or retching, wherein the stomach is evacuated through the esophagus and mouth due to strong muscular contractions in the abdomen. Emesis is usually accompanied by nausea and feelings of strong malaise and discomfort. As used herein, emesis includes vomiting and its related symptoms, such as nausea and malaise.
Emesis can be caused or aggravated by a range of factors, including food poisoning, irritation of the gastrointestinal tract or the nerves that innervate this tract, motion sickness, or severe anxiety. It can also be an undesired side effect of some pharmacological and medical treatments, especially cancer chemotherapy, and radiation therapy. When caused by food poisoning, emesis can be helpful and useful, since it evacuates the stomach and can remove toxins or detrimental microbes. However, in most other situations, emesis is intensely unpleasant and unhelpful. It can be a major problem and can even become life-threatening for people who are already suffering from cancer or other life-threatening illnesses, since it can prevent them from obtaining proper nutrition.
The mechanisms by which vomiting is induced are complex and are not fully understood. However, most cases are believed to involve a reflex circuit, commonly called a reflex "arc," consisting of nerve cells which are linked in series such that when a nerve cell on the receptive end of the arc receives a message, it relays the message on to other nerve cells leading into an emesis center in the brain stem. In the emesis center, nerve cells which are part of the reflex circuit interpret the message and act upon it. For example, the message may have come from sensory cells in the inner ear and may pertain to excessive abnormal motion which, for reasons that are poorly understood, is interpreted by the emesis center as a basis for sending an outgoing command through nerve fibers to muscles in the gastrointestinal tract and abdominal wall. This initiates a coordinated pattern of muscle contractions that constitute the act of vomiting, representing the condition known as motion sickness.
Alternatively, a message may originate in sensory receptors in the gut wall pertaining to a stimulus that is irritating to the gastrointestinal tract. This message is conveyed through nerve fibers from the gut to the emesis center in the brain stem and interpreted as basis for initiating the same outgoing command to commence the act of vomiting. The emesis center functions like a "central switchboard" that serves as the central hub for the incoming and outgoing segments of numerous reflex arcs pertaining to both normal and abnormal gastrointestinal motility, normal motility being the peristaltic wave movements of the gut wall that facilitate processing of food, and abnormal motility being reverse peristaltic movements that are first perceived as nausea and then, as they become more vigorous, as retching and/or vomiting.
Under conditions of extreme anxiety or stress, messages from higher brain centers pertaining to a feeling of being overwhelmed or defeated are conveyed to the emesis center which may interpret the situation as a basis for emesis, perhaps as a primitive response intended to purge the organism of whatever is causing the stress.
An emesis chemoreceptor trigger (ECT) zone has been identified (Borison and Brizzee, 1951; Borison and Wang, 1953) in the same general region of the brain stem where the emesis center is located. The ECT zone is located specifically in a region designated anatomically as the area postrema, which is recognized as one of several circumventricular organs (CVO's) that exist within the brain. CVO's are specialized brain regions that are distinguished from all other regions of the central nervous system (CNS) by the fact that they do not have blood brain barriers (BBB) to prevent substances circulating in the blood from freely entering these brain regions (Rapoport, 1976). Thus, unlike the remainder of the CNS which has BBB that screen substances and only allow certain agents to enter, CVO's are freely accessible to any substances circulating in the blood.
It has been postulated that neurons in the area postrema ECT zone serve as sensors of noxious substances circulating in the blood. Thus, after such a substance has been ingested and begins to be absorbed into the blood, it will enter the area postrema ECT zone and be sensed as a harmful substance. That triggers a message to evacuate the gastrointestinal tract, thereby ridding the body of any remaining noxious substance in the gut. Whether the ECT zone truly functions in this manner is not well established. However, it appears clear that ECT neurons, like other neurons in the general region of the brain stem emesis center, can mediate the act of vomiting.
In the study of potential anti-emetic drugs, the lab animals appropriate for use are ferrets, dogs, cats and monkeys, since these species have a vomit reflex comparable to humans. Rodents and rabbits are not used, since they do not have such a vomit mechanism. Ferrets have become the preferred specie for such research; although they are smaller, less expensive, and require smaller amounts of drugs (some of which are scarce and quite expensive) than dogs or monkeys, ferrets respond in a similar manner (by exhibiting active vomiting as well as malaise and lethargy) to emetic stimuli that induce symptoms in dogs, monkeys, and humans (Florczyk et al, 1982).
As used herein, terms such as "anti-emetic" and "suppression of emesis" apply to a pharmaceutical agent that can reduce, ameliorate, or eliminate one or more symptoms of at least one type of emesis. Various efforts have been made to develop anti-emetic drugs. However, most drugs developed to date are only weakly or moderately effective as anti-emetics and are useful for controlling only certain types of emesis. Moreover, since most such agents interact with many physiological systems in addition to those relevant to the regulation of vomiting, they tend to have undesirable side effects when used at doses required to suppress nausea and vomiting.
Drugs classified as anti-histaminics, such as dimenhydrinate (trade name Dramamine), and anticholinergics, such as scopalamine, have been used for years to prevent motion sickness or the related condition, vertigo (dizziness), which is a prominent symptom of Meniere's disease. However, these agents are relatively ineffective unless taken before a boat or airplane ride or other motion begins, or before the onset of vertigo in Meniere's disease. In addition, they are not effective in suppressing nausea and vomiting caused by other factors (Goodman and Gilman, 1975).
Several approaches have been employed for ameliorating nausea and vomiting associated with cancer chemotherapy. Traditionally, phenothiazines such as compazine and butyrophenones such as haloperidol have been used because it has been thought that dopamine receptors in brain stem regions associated with the emesis center are involved in vomiting, and these agents block dopamine receptors. Results with these agents have been disappointing; they are only weakly active as anti-emetics and must be used at high doses which stimulate numerous dopamine receptors throughout the brain. This results in severe side effects such as abnormal motor movements, muscle rigidity, and tremors.
Over the past decade, another type of dopamine antagonist, metoclopramide (trade name Reglan) has emerged as the agent of choice for suppressing emesis associated with cancer chemotherapy. Although it represents a moderate improvement over prior therapies, it is only partially effective even when used at doses associated with the same disagreeable side effects that other dopamine receptor antagonists typically cause. Recent evidence suggests that the anti-emetic properties of metoclopramide may be explained, not by an effect at dopamine receptors, but rather by an effect at serotonin receptors. Serotonin is the common name for 5-hydroxytryptamine, 5-HT, and the 5-HT system is often called the serotonergic system. Serotonin receptors are divided into three classes; one class is referred to as 5-HT M receptors. Metoclopramide, in addition to being a dopamine antagonist, is able to antagonize 5-HT M receptors (Miner and Sanger, 1986). Metoclopramide is only a weak 5-HT M receptor antagonist, which explains why it has been an effective anti-emetic only when used at high doses.
Recent evidence suggests that certain other agents within the 5-HT M antagonist class, such as BRL 43694 (which is a more powerful and selective 5-HT M receptor antagonist than metoclopramide), may prove more, useful for controlling nausea and vomiting caused by cancer drug therapy. BRL 43694 was shown to be effective in preventing or reducing the severity of emesis in ferrets treated with cisplatin (Bermudez et al., 1988). Cisplatin is an effective cancer chemotherapy drug; it is also a preferred agent for animal testing of anti-emetic drugs, since it is a particularly strong emetic agent in both humans and certain animals such as the ferret.
Very recently, Cassidy and colleagues (1988) conducted a human clinical trial in which BRL 43694 was administered to 20 cancer patients to test its ability to counteract the emetic properties of various drugs being used to treat cancer. The authors considered the results generally promising in that 7 patients experienced neither nausea nor vomiting, 4 had mild nausea, and 9 patients had both nausea and vomiting but it appeared to be delayed in onset. It is too early to predict whether BRL 43694, or other agents in its class, will represent a substantial improvement over other anti-emetics currently available. A limitation of the study by Cassidy et al is that there was no control group to establish the expected incidence of nausea and vomiting in patients receiving identical cancer chemotherapy without an anti-emetic. Moreover, only 5 of the 20 patients received cisplatin; the others received cancer drugs that are not as strong in emetic properties as cisplatin. Of the 5 patients that received cisplaten, 4 suffered from nausea and vomiting.
While it seems likely that 5-HT M receptor antagonists such as BRL 43694 will prove more effective than anti-emetics previously available for cancer chemotherapy patients, there is still a pressing need for additional agents that are more effective by themselves, or that can be used in conjunction with 5-HT M receptor antagonists to provide better anti-emetic therapy. This goal could best be achieved by finding new agents that prevent nausea and vomiting by a different mechanism than that underlying the anti-emetic properties of the 5-HT M receptor antagonists or other currently available anti-emetics.
It is believed that the locus of action of 5-HT M receptor antagonists is at the level of the gastrointestinal tract (Hawthorn et al., 1988). Enterochromaffin cells in the gut are thought to be irritated (stimulated) by cancer chemotherapy agents, which results in the release of large amounts of 5-HT from these cells. The 5-HT stimulates 5-HT M receptors which are present on nerve endings in the gut wall. This stimulus is communicated through nerve fibers to the emetic center in the brain stem which, as described above, serves as a central switchboard for receiving such messages and responding by initiating a vomit response. By blocking the 5-HT M receptors in the gut, 5-HT M receptor antagonists appear to prevent the message from being relayed from the gut to the emesis center in the brain stem. Therefore, the emesis reflex circuit is broken in its initial segment.
It has also been suggested that the 5-HT M antagonists might act directly upon neurons in the brain stem emesis center (Hawthorn et al 1988). However, there is no evidence to substantiate this proposal, since it has not been possible to demonstrate that there are any 5-HT M receptors in this or any other part of the CNS.
As will be discussed below, in seeking to develop more effective anti-emetics, it would be particularly advantageous if a means could be found for interrupting various types of emesis reflex arcs at the level or location of the central switchboard. Since differing reflex arcs pertaining to different types of emetic stimuli apparently pass through a common point or region in the emesis center in the brain stem, a selective blockade involving that region might be effective in blocking more than one type of emesis reflex. Since this would involve an action by a drug within the CNS, any such action should be regionally selective for the brain stem emesis center and should not involve interactions throughout the remainder of the CNS where unwanted side effects might be generated. A method and a pharmacological agent for achieving this type of anti-emetic therapy is the subject of the invention described herein.
Years ago, it was discovered that two common amino acids, glutamate (the ionized or salt form of glutamic acid, abbreviated Glu) and aspartate (the ionized or salt form of aspartic acid, abbreviated Asp) induce vomiting when present in the blood in high concentrations. The emetic properties of Glu and Asp in humans were first discovered when protein hydrolysates containing high concentrations of these two amino acids were administered intravenously for nutritional purposes to patients who could not take food by mouth. It was found that the hydrolysate solution could not be administered rapidly, or it triggered vomiting. Subsequent studies identified the responsible agents as Glu and Asp (Unna and Howe, 1945; Madden et al., 1945; Levey et al., 1949). Over the past decade, Glu and Asp, which are present in high concentration in the CNS, have become recognized as major neurotransmitters that account for the vast majority of the excitatory neurotransmitter activity in the mammalian CNS (reviewed by Olney, 1989).
The standard method by which nerve cells communicate with one another and perform the information processing functions of the CNS is by chemical neurotransmission in which a chemical transmitter molecule is released from a fiber ending of a neuron into the extracellular fluid. While in the extracellular fluid, the transmitter molecule acts upon a membrane receptor molecule on the external surface of another neuron. Several chemical transmitter systems have been identified in the mammalian CNS, including the dopaminergic system referred to above, in which dopamine is the transmitter chemical involved, and the serotonergic system, in which 5-HT (a synonym for serotonin) is the transmitter chemical. For each transmitter system, several receptor subtypes have been identified. For example, although 5-HT M receptors have been found only outside the CNS, two other serotonin receptor subtypes have been clearly demonstrated within the CNS, and there are at least two subtypes of dopaminergic receptors in the CNS. The Glu and Asp transmitter systems are exclusively excitatory; i.e., the action of a Glu or Asp molecule at a receptor triggers or facilitates neuronal activity. By contrast, most other transmitter systems, including the dopaminergic and serotonergic systems, are primarily inhibitory (they suppress neuronal activity) and only occasionally excitatory.
Glu and Asp are identical in their excitatory transmitter activities and, since Glu is found in much higher concentration in the CNS than Asp, the Glu/Asp excitatory transmitter system is often referred to as the Glu transmitter system or, alternatively, as the excitatory amino acid (EAA) transmitter system. Certain structural analogs of Glu and Asp, although not found naturally in the CNS, are also referred to as EAA's because they mimic the neuroexcitatory actions of Glu and Asp when brought in contact with EAA neuronal membrane receptors.
Three subtypes of EAA receptors have been identified, each type being named after a certain Glu analog which preferentially binds to and activates that type of receptor. These receptor subtypes are N-methyl-D-aspartate (NMDA) receptors (preferentially sensitive to NMDA), kainic acid (KA) receptors (preferentially sensitive to KA) and quisqualic acid (Quis) receptors (preferentially sensitive to Quis).
In addition to the important neurotransmitter functions performed by Glu and Asp, these compounds are known to have powerful neurotoxic effects (reviewed in Olney, 1989). This was first learned years ago when these compounds were administered subcutaneously to immature animals of various species, including monkeys, and were found to destroy neurons in specific brain regions, referred to above as CVO brain regions. The reason for the neurotoxic reaction being restricted to CVO brain regions is that Glu and Asp are prevented by BBB from entering other brain regions; since CVO regions lack BBB protection, Glu and Asp had free access to neurons in these regions. Subsequent research established that a neuroexcitatory mechanism underlies the neurotoxicity of Glu and Asp. Although Glu and Asp are beneficial and vitally important substances for excitatory neurotransmitter functions in the CNS, if EAA receptors are exposed to these agents in abnormally high concentrations or for prolonged periods, it literally excites the neuron to death. Thus, Glu and Asp are commonly referred to today as excitotoxins.
Although Glu exists in high concentration in the CNS, it is normally confined inside neurons and is released into the extracellular fluid only for transmitting a nerve message from one neuron to another. For this purpose, it is released only in small amounts, and only long enough to contact an EAA synaptic receptor on the surface of another neuron, thereby exciting (i.e., triggering impulse conduction in) the receiving neuron. After impulse conduction, the excitatory action is terminated very quickly by rapid transport of Glu back inside the cell by an energy-dependent transport mechanism. Under abnormal conditions, when energy supply to the brain is deficient (e.g., after a stroke or cardiac arrest, or during perinatal asphyxia), the energy-dependent transport mechanism begins to fail and Glu is allowed to accumulate in abnormal concentrations at EAA receptors. This leads to overstimulation of neurons, which causes them to release more Glu. This can provoke a cascade of Glu release and neuronal hyperstimulation, which can lead to wholesale destruction of CNS neurons.
The involvement of Glu and Asp in these and other possible neurodegenerative disorders has generated a great deal of interest in the development of EAA receptor antagonists as potential neuroprotective drugs which, by blocking EAA receptors, might be able to prevent neuronal degeneration under abnormal conditions such as the above. Numerous agents have been identified that act as specific NMDA receptor antagonists. The majority of these agents, such as D-2-amino-5-phosphonopentanoate (D-AP5), D-2-amino-7-phosphonoheptanoate (D-AP7), CGS 19755, CPP and CPP-ene (Olney, 1989; Boast, 1988; Herrling et al., 1989) do not readily penetrate blood brain barriers and, therefore, have been considered of limited interest as neuroprotective drugs. NMDA antagonists such as phencyclidine (PCP) and MK-801 which readily penetrate BBB have attracted more attention and, in animal experiments, have been shown to exert powerful neuroprotective effects in conditions such as cerebral ischemia (stroke) (Olney, 1989). The ability of these agents to enter brain and interact with NMDA receptors throughout the brain, however, makes them subject to a number of serious side effects, including psychotic disturbances and pathomorphological changes in cerebrocortical neurons (Olney, 1989; Olney et al., 1989).
Fewer advances have been made in developing antagonists for the Quis and KA receptor subtypes. However, kynurenic acid and its chlorinated derivative, 7-chloro-kynurenic acid, are effective broad-spectrum antagonists that block all three subtypes of EAA receptors (NMDA&gt;KA&gt;Quis) (Olney, 1989). Certain types of quinoxalinediones, including 6,7-dinitro-quinoxaline-2,3-dion (DNQX; also referred to as FG 9041) and 6-nitro-7-cyano-quinoxaline-2,3-dion (CNQX; also referred to as FG 9065) were recently described as the first available agents that block non-NMDA receptors substantially more powerfully than NMDA receptors (Honore et al, 1987; also see Honore et al, 1988, and Drejer and Honore, 1988). These quinoxalinediones are significantly more powerful than kynurenic or 7-chloro-kynurenic acid, but neither group has generated much interest as neuroprotective drugs, since they do not penetrate blood-brain barriers.
It is of interest to review the early literature pertaining to Glu and Asp as emetic agents, in light of other information developed more recently regarding their neuroexcitatory and neurotoxic properties. The fact that Glu and Asp, when administered subcutaneously to experimental animals, had neurotoxic effects on neurons confined to CVO brain regions (including the area postrema, which is within the same general brain region where the ECT zone and emetic center are located) signifies that these excitotoxins entered these brain regions and stimulated these neurons, initially causing them to fire nerve impulses excessively, and eventually causing them to die from excessive stimulation. It has been observed in species such as dogs and monkeys, which are subject to an emetic reflex similar to that in the human, that a toxic dose of Glu or Asp first causes the animal to vomit before continued excitatory stimulation destroys the area postrema-CVO neurons (Olney et al., 1972; Olney and Rhee., 1978).
Based on a study of the literature, several possibilities and hypotheses suggested themselves to the inventor. It appeared likely that Glu and Asp induce emesis in monkeys and dogs (and in humans) by stimulating EAA receptors on the surfaces of area postrema-CVO neurons (the same receptors through which they kill these neurons), which implies that these neurons are connected to an emesis reflex circuit. This raised the question of whether the receptors being stimulated by subcutaneously administered Glu in these animal experiments functioned physiologically by receiving emetic messages from Glu-containing neurons in an emesis reflex circuit. If this were the case, then these Glu-receptive neurons might be an integral link in an emesis reflex circuit, and blocking such receptors with EAA antagonists might interrupt the emesis reflex circuit, and might prevent various other stimuli feeding into the emesis circuit from inducing emesis. Depending on how many types of emetic circuits include an obligatory link comprised of area postrema Glu-receptive neurons, and depending on the types of Glu receptors involved, numerous types of emesis initiated by different stimuli might be suppressed by treatment with a given EAA antagonist. However, if the EAA receptors on the surfaces of area postrema CVO neurons are there only for the purpose of interacting with Glu circulating in the blood, then an EAA antagonist circulating in the blood might block the action of circulating Glu on these neurons without having any effect on circuits regulating other types of emesis.
The experiments described below were undertaken to explore the hypothesis that area postrema CVO neurons are part of a reflex arc from the gut to the brain stem and back to the gut. Based on the results of those experiments, it was discovered that intravenous administration of Glu antagonists can prevent at least some types of emesis by interrupting this reflex arc.
The invention described herein entails control of nausea and vomiting by a mechanism that has never previously been exploited for this purpose. Despite considerable research in the EAA field, and despite many efforts to develop anti-emetic drugs, there are no published reports pertaining to the use of any EAA antagonists as anti-emetic drugs, nor any published reports indicating that EAA antagonists are able to prevent emesis of any kind. Therefore, the invention disclosed herein represents the discovery of an entirely new method for preventing nausea and vomiting, different from any previously described method.
An important feature of this invention is that the locus of action of the EAA antagonists used as described herein is at the level of the "central switchboard" (the emesis center) in the brain stem, where different types of EAA receptors have been shown to participate in the regulation of emesis. Therefore, it is believed by the inventor that several different kinds of vomiting can be controlled by different combinations of EAA antagonists, and that most or all types of vomiting that are not adequately controlled by currently available approaches can be controlled by use of EAA antagonists, alone or in combination with other currently available drugs.
It should be noted that other anti-emetic drugs tend to be useful for controlling only one type of emesis. For example, anti-histaminics are useful only for motion sickness, and not for emesis associated with cancer chemotherapy. 5-HT M receptor antagonists are not effective for motion sickness (Stott et al., 1989) but are somewhat effective for emesis associated with specific cancer chemotherapy drugs, such as cisplatin, that release 5-HT from enterochromaffin cells in the gut. These agents block the emetic stimulus at or near the beginning point, i.e., at the 5-HT receptor site in the gut that receives the original message and sends it through the initial segment of the reflex arc going up to the brain stem. EAA antagonists also block cisplatin-induced emesis, but they do so at the brain stem level by preventing messages transmitted by incoming nerve fibers from being relayed to neurons that transmit outgoing messages to the abdomen, resulting in vomiting. Therefore, the action of EAA antagonists is not limited to a specific mechanism pertaining to the incoming limb of a single reflex arc, as is the case for 5-HT M antagonists; instead, EAA antagonists act at the central switchboard level, where suppression of emesis induction between incoming and outgoing branches of various different emesis reflex arcs appears to be possible. Accordingly, the use of EAA antagonists has potentially wide application for the control of nausea and vomiting.
An additional special feature of this invention is that it takes advantage of the fact that certain Glu antagonists do not penetrate blood brain barriers and cannot enter most regions of the brain proper or the remainder of the CNS. However, they do penetrate select brain regions containing the specific receptors which must be blocked in order to effectively interrupt emesis reflex circuits. The fact that the Glu antagonists do not enter the brain except in the CVO regions signifies that they are much less likely to cause significant side effects than if they were able to interact with Glu receptors throughout the brain, most of which are directly involved in vital functions that are unrelated to emesis regulation.